Elephantiasis, also known as lymphatic filariasis or as a symptom of lymphatic filariasis, is a parasitic infectious disease that is being tackled by several countries across the globe. Specifically, the World Health Organization's () Global Programme to Eliminate Lymphatic Filariasis (GPELF) and America's own USAID's Neglected Tropical Disease Program have been connecting a global health strategy to eliminate this tropical disease that wreaks havoc on the lymphatic system and causes crippling disfigurement. This disease is prevalent in Africa and India, where two-thirds of 120 million infected people are located. The remainder of people are located in northeastern South America [5]. Neglected tropical diseases are one of the world's biggest health challenges; however, modern medicine makes advancementsday by day to solve this problem. Figure 1) Geographical distribution of lymphatic filariasis. Lymphatic filariasis is a quiet disease transferred person to person through mosquito bites. When the mosquito bites the skin, larvae comes in contact with the human body. Larvae then travel to lymphatic vessels and eventually become lodged in the lymphatic system [4]. The larvae stay lodged in the lymphatic system, maturing to adult worms. These worms can live in the lymphatic system for five to seven years. This gives the larvae time to mature into adults, reach puberty, and create mating nests that create further blockage in the lymphatic system [4]. When the worms mate, they create larvae that enter the bloodstream and disrupt the immune system. Three types of worms are most common in causing this infection: Wuchereria bancrofti, responsible for approximately ninety percent of known cases; Brugia malayi, which causes most of the remainder of the cases; and B. timori, which also causes the disease [4]. Many people with lymphatic filariasis never experience any visually apparent symptoms. The parasite can live for years in its host without the host being aware of the infection. Although symptoms may not be seen, a person carrying the parasite can experience side effects of a damaged lymphatic system, damaged kidneys, and an altered immune system [4]. Mild physical symptoms result in lymphoedema. The worst physical symptom is severe lymphoedema, or elephantiasis, which is the face of lymphatic filariasis. The blockage in lymphatic vessels causes an immune response and inflammation in the body. The legs, scrotum, and breasts are the areas of the body that are the most severely affected by elephantiasis, which cause unbearably noticeable deformities [5]. Countries lacking proper medical technique or easily available treatment are where the most severe effects of lymphatic filariasis occur. The physical appearance of elephantiasis causes the afflicted person to most likely be rejected in societal situations, resulting in a social stigma [4]. This horrible deformity leads to further hardship on families. Not only do infected individuals have health problems and medical bills, but they are also rejected from society. This leads to unemployment, loss of income, and destitution.Figure 2) The cycle of parasitic infection between mosquitoes and humans. TARGET INFORMATION
The way that antifilarial drugs interact with lymphatic filariasis is not well known, and scant information is readily available discussing the exact mode of action that the drugs take to inhibit its target. However, DEC is known to be an inhibitor of the arachidonic acid mechanism in microfilariae circulating through the human bloodstream [2]. DEC is microfilaricidal, or more effective in killing larvae, and is not as effective, if not completely ineffective, on adult worms. Arachidonic acid (304.47 grams per mole) is a fatty acid present in filarial lipid bodies. In humans, it is present in the phospholipids of body cells and acts as a secondary messenger of cellular signaling [2]. It is not necessary in humans, but inhibiting the filarial arachidonic acid metabolic pathway in has a significant effect. DEC alters the filarial arachidonic acid metabolism in microfilariae, resulting in narrowing of filarial vessels resulting. This is due to contraction of muscular walls and increased endothelial adhesion, which immobilizes microfilarial parasites. The immune system of the larvae is left vulnerable to damage [2].
Figure 3) The filarial arachidonic acid metabolic pathway is incredibly complex. DEC alters this pathway to immobilize the parasites.
DRUG INFORMATION
The accepted drug for treatment in the United States is diethylcarbamazine citrate (DEC). Diethylcarbamazine (CAS Number 90-89-1) has a molecular weight of 199.293 grams per mole. DEC has been recognized as an anti-filarial drug since 1947, when it was tested against lymphatic filariasis and determined to be safe for human treatment [1]. After several studies, DEC was released for human use against filarial infection in the mid 1970's with the dosage of 72 mg/kg of body weight. This cumulative dosage was split into twelve separate doses [1]. Depending on the infection, the dosages could be taken either weekly or monthly at 6 mg/kg of body weight. In the 1990's, studies supported the idea of low-dosage DEC distribution. Currently, people with filarial infections take a 6 mg/kg of body weight dose of DEC once annually [1]. This is the dosage plan being followed by global health organizations targeting lymphatic filariasis at this time [4]. DEC is a synthetic drug mostly specific to antifilarial use, but to a certain extent it also treats eosinophilic lung, loiasis, and river blindness (onchocerciasis) [4]. DEC is an extremely effective drug, decreasing the amount of filarial larvae present in the bloodstream in just minutes. However, it does not completely destroy the parasitic infection since it is not entirely effective against adult worms. Diethylcarbamazine can be used in any geographic region of infection, although a different drug is chosen for treatment with the ability to further treat additional diseases if additional diseases exist in the selected infected region. The preferred mode of treatment with DEC is the ingestion of a tablet, though it can be made as a syrup or white, crystalline powder. There are several common side effects of DEC including headache, joint pain, tiredness or weakness, dizziness, and nausea [4]. Itching and swelling of the face; fever; painful and tender glands in the neck, armpits, or groin; and skin rash are common effects, but more serious side effects also exist. Perhaps the most serious side effect is loss of vision and the development of severe night blindness [5]. DEC is marketed as a dicitrate salt, and the most commonly used brand name in the United States is Hetrazan. Currently, there are no patents pending on this compound, and no existing patents were detected. Eleven clinical trials that involve the treatment of DEC for filariasis are listed by the U.S. National Institutes of Health .DEC is found to be more effective when used in combination with the drug albendazole, which is a well-known anti-intestinal helminths agent [3]. The World Health Organization's GPELF incorporates the two drugs together with the standard dose for DEC and a 400 mg dose of albendazole. This kind of treatment combination is common in areas affected by this disease. In onchocerciasis endemic countries in Africa or other areas, a combination of albendazole and a 150-200 mcg/kg of body weight dose of ivermectin is used completely in place of DEC [4]. Albendazole is macrofilarial agent that inhibits temperature-sensitive protein Z (FtsZ), meaning that it has the ability to kill the adult worms that cause blockages and produce the larvae that cause lymphoedema. Using DEC and albendazole together is an effective treatment because together they attack both the adult worms and the larvae. This combination effectively destroys the infection and permanent symptoms must be taken care of by increased thoroughness of personal hygiene. Figure 4) Structure of diethylcarbamazine. The molecular formula of DEC is C10 H21 N3 O.
REFERENCES
[1] Kimura, E., The Global Programme to Eliminate Lymphatic Filariasis: History and achievements with special reference to annual single-dose treatment with diethylcarbamazine in Samoa and Fiji. Tropical Medicine and Health 2011, 39, (1), 17-30.
[2] McGarry, H. F.; Plant, L. D.; Taylor, M. J., Diethylcarbamazine activity against Brugia malayi microfilariae is dependent on inducible nitric-oxide synthase and the cyclooxygenase pathway. Filaria Journal 2005, 4: (4), 1-9.
[3] Sharma, R.; Hoti, S.L.; Vasuki, V.; Sankari, T.; Meena, R. L.; Das, P. K., Filamentation temperature-sensitive protein Z (FtsZ) of Wolbachia, endosymbiont of Wuchereria bancrofti: A potential target for anti-filarial chemotherapy. Acta Tropica 2013, 125, (3), 330–338.
DISEASE/DRUG OF INTEREST
Elephantiasis/Diethylcarbamazine citrate (DEC)The deformities caused by elephantiasis are physically and socially disabling [6].
Video Link: http://www.cartercenter.org/news/multimedia/HealthPrograms/AlleviatingSufferingEndingShame.html
MOTIVATION AND BACKGROUND
Lymphatic filariasis is a quiet disease transferred person to person through mosquito bites. When the mosquito bites the skin, larvae comes in contact with the human body. Larvae then travel to lymphatic vessels and eventually become lodged in the lymphatic system [4]. The larvae stay lodged in the lymphatic system, maturing to adult worms. These worms can live in the lymphatic system for five to seven years. This gives the larvae time to mature into adults, reach puberty, and create mating nests that create further blockage in the lymphatic system
Countries lacking proper medical technique or easily available treatment are where the most severe effects of lymphatic filariasis occur. The physical appearance of elephantiasis causes the afflicted person to most likely be rejected in societal situations, resulting in a social stigma [4]. This horrible deformity leads to further hardship on families. Not only do infected individuals have health problems and medical bills, but they are also rejected from society. This leads to unemployment, loss of income, and destitution.Figure 2) The cycle of parasitic infection between mosquitoes and humans.
TARGET INFORMATION
The way that antifilarial drugs interact with lymphatic filariasis is not well known, and scant information is readily available discussing the exact mode of action that the drugs take to inhibit its target. However, DEC is known to be an inhibitor of the arachidonic acid mechanism in microfilariae circulating through the human bloodstream [2]. DEC is microfilaricidal, or more effective in killing larvae, and is not as effective, if not completely ineffective, on adult worms.
Arachidonic acid (304.47 grams per mole) is a fatty acid present in filarial lipid bodies. In humans, it is present in the phospholipids of body cells and acts as a secondary messenger of cellular signaling [2]. It is not necessary in humans, but inhibiting the filarial arachidonic acid metabolic pathway in has a significant effect. DEC alters the filarial arachidonic acid metabolism in microfilariae, resulting in narrowing of filarial vessels resulting. This is due to contraction of muscular walls and increased endothelial adhesion, which immobilizes microfilarial parasites. The immune system of the larvae is left vulnerable to damage [2].
DRUG INFORMATION
The accepted drug for treatment in the United States is diethylcarbamazine citrate (DEC). Diethylcarbamazine (CAS Number 90-89-1) has a molecular weight of 199.293 grams per mole. DEC has been recognized as an anti-filarial drug since 1947, when it was tested against lymphatic filariasis and determined to be safe for human treatment [1]. After several studies, DEC was released for human use against filarial infection in the mid 1970's with the dosage of 72 mg/kg of body weight. This cumulative dosage was split into twelve separate doses [1]. Depending on the infection, the dosages could be taken either weekly or monthly at 6 mg/kg of body weight. In the 1990's, studies supported the idea of low-dosage DEC distribution. Currently, people with filarial infections take a 6 mg/kg of body weight dose of DEC once annually [1]. This is the dosage plan being followed by global health organizations targeting lymphatic filariasis at this time [4].
DEC is a synthetic drug mostly specific to antifilarial use, but to a certain extent it also treats eosinophilic lung, loiasis, and river blindness (onchocerciasis) [4]. DEC is an extremely effective drug, decreasing the amount of filarial larvae present in the bloodstream in just minutes. However, it does not completely destroy the parasitic infection since it is not entirely effective against adult worms. Diethylcarbamazine can be used in any geographic region of infection, although a different drug is chosen for treatment with the ability to further treat additional diseases if additional diseases exist in the selected infected region.
The preferred mode of treatment with DEC is the ingestion of a tablet, though it can be made as a syrup or white, crystalline powder. There are several common side effects of DEC including headache, joint pain, tiredness or weakness, dizziness, and nausea [4]. Itching and swelling of the face; fever; painful and tender glands in the neck,
armpits, or groin; and skin rash are common effects, but more serious side effects also exist. Perhaps the most serious side effect is loss of vision and the development of severe night blindness [5]. DEC is marketed as a dicitrate salt, and the most commonly used brand name in the United States is Hetrazan. Currently, there are no patents pending on this compound, and no existing patents were detected. Eleven clinical trials that involve the treatment of DEC for filariasis are listed by the U.S. National Institutes of Health .DEC is found to be more effective when used in combination with the drug albendazole, which is a well-known anti-intestinal helminths agent [3]. The World Health Organization's GPELF incorporates the two drugs together with the standard dose for DEC and a 400 mg dose of albendazole. This kind of treatment combination is common in areas affected by this disease. In onchocerciasis endemic countries in Africa or other areas, a combination of albendazole and a 150-200 mcg/kg of body weight dose of ivermectin is used completely in place of DEC [4]. Albendazole is macrofilarial agent that inhibits temperature-sensitive protein Z (FtsZ), meaning that it has the ability to kill the adult worms that cause blockages and produce the larvae that cause lymphoedema. Using DEC and albendazole together is an effective treatment because together they attack both the adult worms and the larvae. This combination effectively destroys the infection and permanent symptoms must be taken care of by increased thoroughness of personal hygiene.
Figure 4) Structure of diethylcarbamazine. The molecular formula of DEC is C10 H21 N3 O.
REFERENCES
[1] Kimura, E., The Global Programme to Eliminate Lymphatic Filariasis: History and achievements with special reference to annual single-dose treatment with diethylcarbamazine in Samoa and Fiji. Tropical Medicine and Health 2011, 39, (1), 17-30.
[2] McGarry, H. F.; Plant, L. D.; Taylor, M. J., Diethylcarbamazine activity against Brugia malayi microfilariae is dependent on inducible nitric-oxide synthase and the cyclooxygenase pathway. Filaria Journal 2005, 4: (4), 1-9.
[3] Sharma, R.; Hoti, S.L.; Vasuki, V.; Sankari, T.; Meena, R. L.; Das, P. K., Filamentation temperature-sensitive protein Z (FtsZ) of Wolbachia, endosymbiont of Wuchereria bancrofti: A potential target for anti-filarial chemotherapy. Acta Tropica 2013, 125, (3), 330–338.
[4] USAID's Neglected Tropical Diseases. Lymphatic filariasis. http://www.neglecteddiseases.gov/target_diseases/lymphatic_filariasis/ (accessed Feb 1, 2014).
[5] World Health Organization. Lymphatic filariasis. http://www.who.int/mediacentre/factsheets/fs102/ en/ (accessed Jan 29, 2014).
[6] The Carter Center. Lymphatic filariasis (Elephantiasis). http://www.cartercenter.org/news/multimedia/HealthPrograms/AlleviatingSufferingEndingShame.html (accessed Feb. 18, 2014).